Tumor-specific peptide–HLA complex (pHLA)

Tumor-specific peptide–HLA (pHLA) complexes are cell-surface molecules consisting of a short peptide fragment, derived from an intracellular tumor antigen, bound within the groove of a Human Leukocyte Antigen (HLA) molecule. These complexes serve as the primary signal for T-cell recognition, where the T-cell receptor (TCR) binds to the specific peptide-HLA combination to initiate an adaptive immune response against malignant cells (nih.gov, 2026; frontiersin.org, 2025). By presenting fragments of intracellular proteins—including neoantigens from mutations or overexpressed tumor-associated antigens—pHLA complexes allow the immune system to target a much broader range of the proteome than traditional surface-bound antigens (nih.gov, 2016; nih.gov, 2020). Therapeutic strategies targeting these complexes include TCR-engineered T cells (TCR-T), TCR-mimetic (TCRm) antibodies, and bispecific T-cell engagers like Tebentafusp, which are designed to bypass the limitations of conventional antibodies by accessing the intracellular landscape of the cancer cell (nih.gov, 2017; researchgate.net, 2023). However, the high polymorphism of HLA alleles and the potential for lethal cross-reactivity with similar peptides in healthy tissues present significant safety challenges and require precise patient selection based on HLA typing (nih.gov, 2017; frontiersin.org, 2020).

Other names

Peptide-Major Histocompatibility Complex (pMHC)Tumor-associated antigen-HLA complexNeoantigen-HLA complexCancer-specific peptide-HLA complexTCR-mimetic targetHLA-restricted antigen

Drugs targeting these complexes function by utilizing engineered T-cell receptors (TCRs) or TCR-mimetic antibodies to specifically recognize the peptide-HLA combination on the cell surface, which triggers T-cell activation, recruitment of effector cells, and the subsequent release of cytotoxic granules (perforin and granzymes) to induce apoptosis in the target cancer cell.